Allenamides and ynamides, subgroups of heteroatom-substituted allenes and alkynes, have become highly versatile organic synthons applicable to a diverse array of transformations that can be useful for natural product syntheses. In the last ten years, the chemistry of allenamides and ynamides has become an emerging field with contributions from many groups around the world including our own. We have succeeded in identifying allenamides and ynamides as useful equivalents of allenamines and ynamines that possess the right balance between reactivity and stability. We have developed their practical and efficient synthetic access, and implemented these novel functional groups in highly stereoselective inter- and intramolecular reactions that were otherwise difficult, if not impossible, to achieve using allenamines and ynamines. The goals of this NIH renewal are to explore novel tandem methods involving the allenamide chemistry, and to accomplish total syntheses of complex alkaloids featuring stereoselective methods using both allenamides and ynamides. Specifically, we intend to focus on three Aims in this renewal with two in the area of allenamides and one in the area of ynamides: In Aim-1, we intend to develop N-tethered IMDA reactions in tandem with ?-isomerization of allenamides. In Aim-2, we intend to design a series of de novo tandem reaction sequences initiated from allenamide ?-isomerizations. In Aim-3, we intend to pursue a total synthesis of (+)-davisine featuring one of these novel tandem reactions. In Aim-4, we intend to accomplish a total synthesis of (+)-thalbadenzine featuring a Bronsted acid catalyzed tandem keteniminium Pictet-Spengler cyclization involving a macrocyclic bis-ynamide. Having led the efforts in revitalizing interest in a research area that has been largely overlooked, we have a tremendous amount of momentum and are poised not only to continue demonstrating with these new Aims the synthetic utility of chiral allenamides and ynamides as novel functional groups, but more significantly, to take their chemistry to the next level of visibility. PUBLIC HEALTH RELEVANCE: This renewal intends to explore novel methods involving the allenamide chemistry and accomplish the total synthesis of a complex alkaloid featuring stereoselective methods using ynamides. In the last ten years, the chemistry of allenamides and ynamides has become an emerging field with contributions from many groups around the world including our own. Having led the efforts in revitalizing interest in a research area that has been largely overlooked, we have a tremendous amount of momentum and are poised in this renewal, not only to continue demonstrating the synthetic utility of chiral allenamides and ynamides as novel functional groups, but also more significantly, to take their chemistry to the next level of visibility